Modulation of the allergic asthma transcriptome following resiquimod treatment

Abstract

Resiquimod is a compound belonging to the imidazoquinoline family of compounds known to signal through Toll-like receptor 7. Resiquimod treatment has been demonstrated to inhibit the development of allergen induced asthma in experimental models. The aim of the present study was to elucidate the molecular processes that were altered following resiquimod treatment and allergen challenge in a mouse model of allergic asthma. Employing microarray analysis, we have characterized the "asthmatic" transcriptome of the lungs of A/J and C57BL/6 mice and determined that it includes genes involved in the control of cell cycle progression, the complement and coagulation cascades, and chemokine signaling. Our results demonstrated that resiquimod treatment resulted in the normalization of the expression of genes involved with airway remodeling, and generally, chemokine signaling. Resiquimod treatment also altered the expression of cell adhesion molecules, and molecules involved in natural killer (NK) cell-mediated cytotoxicity. Furthermore, we have demonstrated that systemic resiquimod administration resulted in the recruitment of NK cells to the lungs and livers of the mice, although no causal relationship between NK cell recruitment and treatment efficacy was found. Overall, our findings identified several genes, important in the development of asthma pathology, that were normalized following resiquimod treatment, thus improving our understanding of the molecular consequences of resiquimod treatment in the lung milieu. The recruitment of NK cells to the lungs may also have application in the treatment of virally induced asthma exacerbations.

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

“…In a murine asthma model, intranasal application of R848 efficiently inhibited the asthma phenotype, including airway hyperreactivity (AHR), airway inflammation, mucus hypersecretion, and Th2 cytokine production, confirming findings of previous studies in asthma models (18,(23)(24)(25)(26). Furthermore, R848 strongly induced IL-27 secretion, which was crucial for its therapeutic effect as demonstrated by in vivo neutralization of IL-27 via an mAb.…”

“…In these studies, the R848-mediated effect was mostly attributed to its ability to induce IFN-g by NKT, NK, or CD8 + T cells (23,26). However, IFN-g cannot solely account for the protective effect because the R848-mediated protection is neither abolished in IFN-g-deficient mice nor through depletion of NKT cells (23,26).…”

“…However, IFN-g cannot solely account for the protective effect because the R848-mediated protection is neither abolished in IFN-g-deficient mice nor through depletion of NKT cells (23,26). In addition to inducing IFN-g (18), application of R848 enhanced secretion of IL-27 in human and murine cells (27,28).…”

Treatment with the TLR7 agonist R848 induces regulatory T‐cell‐mediated suppression of established asthma symptoms

“…These protective effects were observed after administration of R848 during the sensitization phase, whereas in mice having already mounted a primary allergic response, the treatment resulted in a marked reduction of secondary reactions following repeated allergen aerosol challenges mediated through IL-12 and IL-10 [8,12]. Although IFN-g-producing NK cells have been held responsible for R848-induced asthma protection, it is now clear that they cannot solely account for the protection that is abolished neither by their depletion nor in IFN-g-deficient mice [13,14].…”

“…These protective effects were observed after administration of R848 during the sensitization phase, whereas in mice having already mounted a primary allergic response, the treatment resulted in a marked reduction of secondary reactions following repeated allergen aerosol challenges mediated through 12]. Although IFN-g-producing NK cells have been held responsible for R848-induced asthma protection, it is now clear that they cannot solely account for the protection that is abolished neither by their depletion nor in IFN-g-deficient mice [13,14].Major cellular components driving asthmatic reactions include eosinophils and CD4 In the present study, we investigated the effect of the TLR7 agonist R848 in a murine experimental model of established allergic asthma. We provide evidence that this compound targets pulmonary Tregs, enabling them to exert a protective effect mediated mainly through TGF-b production.…”